Therapeutic modulation of the tumor-promoting immune type 2 microenvironment in malignant glioma by the induction of a type 1 response to attenuated rabies virus
Malignant glioma is an aggressive and invasive tumor associated with a high frequency of M2 polarized tumor associated macrophages and an immunosuppressive tumor microenvironment that promotes tumor growth and function. The unacceptably low survival rates of patients with high grade astrocytoma and glioblastoma have not been improved in decades by standard care. Immune- based therapy seeks to provide better outcomes through various strategies that promote glioma-specific immunity, but many of these strategies have yet to improve long term patient survival. Although the tumor is present within the central nervous system, which is somewhat isolated from the peripheral immune system by the blood-brain barrier, immunity naturally develops in response to glioma antigens. This presumably occurs in part through the release of glioma-derived exosomes, small vesicles containing concentrated tumor-derived cargo, which are found in peripheral fluids. Tumor exosomes generate type 2 biased responses and promote M2 monocyte activation, consequently contributing to tumor supportive macrophage populations. In contrast, the response accompanying neurotropic, attenuated rabies virus clearance from the CNS is associated with the production of type 1 proinflammatory factors in brain tissue, enhanced blood-brain barrier permeability, and effector entry into the CNS. Data presented here indicate that RABV infection can promote both mouse and human glioma exosome- specific Th1 responses, yet glioma exosomes from both species have inherent Th2-biasing properties, likely due to immunoregulatory miRNA content, and can shift the rabies virus response away from Th1. Furthermore, neuroinvasive rabies virus infection of mice with established brain tumors does not impact tumor-specific humoral responses, but prolongs survival and enhances tumor necrosis, primarily by triggering a proinflammatory shift in the tumor microenvironment resulting in re-polarization of tumor associated macrophages. Mechanistically these effects depend on the Th1 immune response to rabies virus as Tbet-/- mice derive no therapeutic benefit from infection. The data show that glioma derived factors fundamentally bias immune responses to Th2, but also highlight the importance of type 1 immune responses in overcoming pro-tumor factors and M2 macrophages in the tumor microenvironment. These findings have implications for the development of effective malignant glioma immunotherapies.
Bongiorno, Emily K, "Therapeutic modulation of the tumor-promoting immune type 2 microenvironment in malignant glioma by the induction of a type 1 response to attenuated rabies virus" (2016). ProQuest ETD Collection - Thomas Jefferson University. AAI10164158.